Project Summary/Abstract Memory impairment occurs in a variety of neuropsychiatric conditions (e.g., depression and schizophrenia) and in many neurologic disorders (e.g., neurodegenerative disease and brain injury), often with devastating consequences for life quality. The goal of this project is to determine optimal dosing parameters for a new procedure involving the noninvasive enhancement of human hippocampal-cortical brain networks that critically support memory. This noninvasive brain-stimulation procedure, ?HFN-Stim?, can produce robust and lasting enhancement of hippocampal-cortical networks and concomitant improvement in long-term memory for up to 15 days after stimulation. However, stimulation parameters have not been optimized. It is yet unknown whether HFN-Stim could be tailored to have greater effects on hippocampal-cortical networks and memory. We therefore propose a collection of experiments that will determine optimal duration, frequency, and context of stimulation by establishing dose-response relationships for each of these three parameters. First, we will determine whether increasing consecutive, daily HFN-Stim sessions (5, 10, and 20 days) produces greater and/or longer- lasting effects on hippocampal-cortical networks and memory. Second, we will determine whether stimulation frequencies matching endogenous oscillatory activity of the hippocampal-cortical network (i.e., theta rhythm) produce greater and/or longer-lasting effects on hippocampal-cortical networks and memory, relative to existing frequencies that have been used for HFN-Stim. Finally, we will determine whether delivery of HFN-Stim while subjects perform a demanding memory task designed to engage the hippocampal- cortical network produces greater and/or longer-lasting effects on hippocampal-cortical networks and memory, relative to performance of a control task that does not robustly engage the hippocampal-cortical network. These research objectives are in close alignment with the focus of RFA-MH-16-815 on establishing dose/response relationships for existing neuromodulation devices to promote neuroscience applications and clinical interventions, specifically RFA Topics 1, 3, and 4 on the duration, frequency, and contextual aspects of stimulation. All proposed experiments involve sophisticated assessments of hippocampal-dependent memory and of hippocampal-cortical brain networks, obtained through simultaneous fMRI/EEG and detailed memory testing. Findings will deeply inform efforts to optimize noninvasive stimulation for the enhancement of hippocampal-cortical networks and memory. This research could propel understanding of memory impairment and its treatment by noninvasive stimulation.